Amines and process for the preparation of amines



United States AMINES AND PROCESS FOR THE PREPARATION F AMINES No Drawing. Application May 9, 19 .9, Serial No. 92,245

Claims priority, application Switzerland May 21, 1948 10 Claims. (Cl. 260-296) The present invention relates to a new process for the preparation of amines from amides with the same number of carbon atoms.

It is old to convert an acid amide, for instance, by the Hofmann degradation, into an amine which contains one carbon atom less than the starting amide. Various methods have also been described in the literature, according to which amides can be reduced to amines having the same number of carbon atoms. Such a reduction can be carried out cataiytically with the aid of a copper-chromium oxide catalyst at a temperature of about 250 C. and at 200 to 300 atmosphere pressure [see Neuerc Methoden der pr'aparativen organischen Chemie, page 132 (Berlin 1943)]. Amides may also be reduced to amides electrolytically ['Fl. Fichter, Organische Elektrochemie, page 265 et seq. (1942)]. These known processes are, however, bound up with disadvantages, particularly since the energetic reaction conditions which they entail give rise to undesired side-reactions. In many cases, it is entirely impossible according to the known methods to reduce amides to the desired amines at all.

A primary object of the present invention is the embodiment of a process for the conversion of amides into amines having the same number of carbons, which process is free of the aforementioned deficiencies of the prior art processes. Briefly stated, this object is realized according to the present invention, in connection with the conversion ofthe carboxylic acid amides to amines, by reducing the starting amide with lithium-aluminumhydride.

The process according to the invention is applicable to a wide variety of amides, so that the initial amide may be a substituted or unsubstituted amide of an aliphatic, alicyclic, aromatic, araliphatic or heterocyclic carboxylic acid. The amide moiety maybe of the open chain type, i. e. of the type of -CONH2, or, as in the case of the cyclic amides, may form part of a ring, as in the lactams, for example the, 2-pyridones or the Z-quinoiones (carbostyrils), and as in the dicarboxylic acid imides, such as the phthalimides; or quinolinic acid imides. The acid moiety of the amide being reduced may be substituted, for example by free or etherified hydroxy groups or by further amide groups, so as to obtain polyamines.

It is preferred, according to the present invention, to efiect the reduction in an indifferent, anhydrous organic solvent medium in which the lithium-aluminum-hydride.

being used is soluble, and in this connection the preferred solvent is ether, although many others such as tetrahydrofurane, butyl ether, dioxane and the like may also be employed. Particularly good results are obtained with amides which are readily soluble in the solvent or diluent medium employed.

The process according to the present invention makes it possible to prepare amines in simple manner, which cannot be obtained at all or only with difiiculty according to known processes, as for example amines whose nitrogen atom is connected with three different organic radicals.

atent An important advantage of the present process is that it is carried out at a relatively low temperature so that side-reactions are thus avoided. In general, carbon-t0- carbon multiple bonds which may be present are not reduced. However, it is possible with suitably selected reaction conditions, for example by the use of increased quantities of reducing agent, extended reaction time and elevated temperature to saturate double bonds in certain cases, particularly double bonds in uzfi-position with respect to tthe amide group. The new process is especially suitable, for example, for the preparation of 2,3-bis- (aminomethyD-pyridines, such as 2,3-bis-(dialkylaminomethyl)-pyridines.

The amines which can be prepared according to the present invention are manifestly suitable for a wide range of uses such as detergents, pharmaceuticals and intermediates for the production thereof.

The invention is hereinafter set forth in greater detail by means of the illustrative examples which follow, but which are not intended to be limitative of the scope of the invention. -In the said Examples the parts are by weight unless otherwise indicated, and the relationship between parts by weight and parts by volume is the same as that between grams and cubic centimeters. The temperatures are in degrees Centigrade.

EXAMPLE 1 Triethylamine 9.5 parts of .lithium-aluminum-hydride are dissolved in 360 parts by volume of absolute ether; and to the resultant solution there are added 23 parts of N,N-diethyl-acetamide, dissolved in 300 parts by volume of absolute ether, at such a rate that the solution continues to boil gently. Upon completion of the reduction, water is added to the reaction mixture, which is also acidified with sulfuric acid and then extracted with ether for the removal of the acid and neutral reaction products. It is then made strongly alkaline with 10 N-caustic soda solution and again extracted with ether. Triethylamine having a boiling point of 89 is obtained from the ether extract.

EXAMPLE 2 Ethyl-propylamine 44 parts by weight of propionic acid-ethylamide in 600 parts by volume of absolute ether are added to 19 parts of lithium-alurninum-hydride in 720 parts by volume of absolute ether. Upon completion of the reaction further manipulation is carried out according to Example 1, and there is obtained ethyl-propylarnine having a boiling point of 78. .lts hydrochloride melts at ZZZ-223.

EXAMPLE 3 ,B-Ethylbutylamine EXAMPLE 4 N- (3,4,5 -trimeth oxy-benzyl -aimethylamine Proceeding in a manner analogous to that described in Example 4, there is obtained from 12 parts of 3,4,5-trimethoxy-benzoic acid-dimethylamide, by reduction with 4.6 parts of lithium-aluminum-hydride, the N-(3,4,5 -trimethoxy-benzyl)-dimethylamine having a boiling point at 10 mm. pressure of 154155. From this amine, there can be obtained the picrate having a melting point of 146 147 EXAMPLE 5 B-phenyl-e thylamin e 4.5 parts of lithium-'aluminum-hydride are dissolved in 500 parts by volume of absolute ether and 13.5 parts of phenylacetamide in an extraction shell are added thereto. The ethereal solution is heated until all the phenyl-acetamide is extracted. Then the process set forth in the preceding examples is followed and there is obtained B-phenyl-ethylainine which boils at 78-80 under a pressure of 12 mm, and the picrate of which melts at 167163.

EXAMPLE 6 lso-ilzdolz'ne Upon "proceeding analogousl to the method described in the preceding example, 9.0 parts of lithium-aluminumhyd'ride are dissolved in 600 'parts by volume of absolute ether and 14.7 parts of phthalimide in an extraction shell are introduced. In the course of the extraction, the contents of the flask become brownish-black. Upon working up the reaction mixture as in the preceding examples, iso-indolirie having a boiling point of 92 at 10 mm. pressure is obtained; its picrate forms fine needles which melt at l92l93.

EXAMPLE 7 N -ethyl-decahydro-isoquinoline To 4.54 parts of lithium-aluminum-hydride in 300 parts by volume of absolute ether, 8.95 parts of N-acetyl-decahydro-isoquinoline dissolved in 300 parts by volume of absolute ether are added dropwise in such manner that the i ether boils gently. Upon completion of the reaction, further proceeding is effected in accordance with the preceding examples, and there is thus obtained N-ethyl-decahydro-isoquinoline which boils at 9294 at 12 mm. pressure. It forms a hydrochloride which melts at 203-204".

EXAMPLE 8 2,3-bis (N-ethyl-N-benzyl-aminomethyl) -pyridine A solution of parts of quinoline acid-bis-benzyl-ethylamide and 300 parts by volume of absolute ether is allowed to flow into 14.2 parts of lithium-aluminum-hydride in 300 parts of absolute ether. The contents of the flask immediately undergo a yellow coloration and boil gently. The addition is extended over a period of 2 hours. The reaction mixture is then heated for 22 additional hours on the water bath. After working up in accordance with the preceding example, 2,3-bis-(N-ethyl-N-benzyl-aminomethyl)-pyridine is obtained as a colorless oil which boils at 78-80 under a pressure of 12 mm. its hydrochloride melts at 179480".

EXAMPLE 9 1 ,2,3,4-tetrahydro-isoquinoline 14.7 parts of isodehydrocarbostyril, dissolved in 300 parts by volume of absolute ether, are added dropwise within a period of two hours to the solution of 4.75 parts of lithium-aluminum-hydride in 300 parts by volume of absolute ether. Heating is then continued for 24 more hours at a bath temperature of The process is then carried 'out in accordance with the preceding examples and the desired base, 1,2,3,4-tetrahydro isoquinoliue, is distilled at 106l08 under a pressure of 12 mm. The hydrochloride has a melting point of 192-193".

EXAMPLE l0 9-aminomethyl-phenanthrene 10.5- pans er 9-phenanthryl-c arboxylic acid-amide are introduced into an extraction shell. A solution of 3.5 parts of lithiuiii aliirhiiium-hyd'ride 500 parts by volume Cir of absolute ether, in the apparatus; is heated until the shell is empty. After working up in accordance with the preceding example, there is obtained the 9-aminomethylphenanthrene which melts at 170.

EXAMPLE 11 fi-difnethylaminoerhyl-benzhydryl ether 27 parts of diphenylmethoxy-acetic acid-dimethylamide, in parts by volume of absolute ether, are added dropwise to the solution of 4.2 parts of lithium-aluminumhydride in 400 parts of absolute ether. After working up in accordance with previous examples, B-dimthylaminoethyl-benzhydryl ether is obtained as an oil which boils at 122-125" at 0.1 mm. pressure. The hydrochloride melts at 159-160"; the picrate at -128.

EXAMPLE 12 ot-Plzen0xy-ethylamine 6.9 parts of phenoxyacetamide are added dropwise to a solution of 4.6 parts of lithium-aluminum-hydride in 600 parts by volume of absolute ether, at such a rate that the solution boils gently. Upon completion of the reaction, the reaction mixture is decomposed with water, and the reaction mass, after acidification with sulfuric acid, is then extracted with ether. Thercupon it is made alkaline and again extracted with ether. This ether extract yields the ,B-phenoxy-ethylamine having a boiling point at 12 mm. pressure of 104. its picrate melts at 167-168".

What We claim is:

l. A process for the preparation of an amine, which comprises reducing a carboxylic acid amide containing at least once the grouping, such grouping being the sole reducible part of said amide, to an amine which has the same number of carbon atoms, by reacting it with lithium-aluminumhydride in an anhydrous organic solvent which is inert under the reaction conditions, as the reaction medium, and at an elevated temperature decomposing the resulting reaction mixture with an aqueous medium, and isolating the amine which is formed.

2. A process for the preparation of an amine, which comprises reducing a carboxylic acid amide containing at least once the grouping, such grouping being part of a ring and constituting the sole reducible part of said amide, to an amine which has the same number of carbon atoms, by reacting it with lithium-aluminum-hydride in an anhydrous organic solvent which is inert under the reaction conditions, as the reaction medium and at an elevated temperature, and isolating the amine which is formed.

3. A process for the preparation of an amine, which comprises reducing a carboxylic acid amide containing at least once the grouping, such grouping being part of a straight chain and constituting the sole reducible part of said amide, to an amine which has the same number of carbon atoms, by reacting it with lithium-aluminum-hydride in an anhydrous organic solvent which is inert under the reaction conditions, as the reaction medium and at an elevated temperature decomposing the resulting reaction mixture with an aqueous medium, and isolating the amine which is formed.

4. A process according to claim 2, wherein the starting compound to be reduced is a laetarn.

5. A process according to claim 2, wherein the starting compound to be reduced is a dicarboxylic acid imide.

6. A pyridine containing, as sole substituents, an N-lower-alkyl-N-aralkyl-substituted aminoethyl group in each of the 2- and 3'positions.

7. 2,3 bis (N ethyl N benzyl aminomethyl) pyridine.

8. A process for the preparation of a pyridine which contains, as sole substituents, an N-lower-alkyl-N-aralkyl-substituted aminomethyl group in each of the 2- and 3-positions, which comprises reducing the corresponding quinolinio acid-bis-aralkyl-alkylamide to the amine by reacting the amide with lithium-aluminum-hydride in an anhydrous organic solvent which is inert under the reaction conditions, as the reaction medium, and at an elevated temperature, and isolating the resultant amine.

9. A process for the preparation of 2,3-bis-(N-ethyl- N-benzyl-aminomethyl)-pyridine, which comprises reducing quinolinic acid-bis-benzyl-ethylamide to the said pyridine by reacting the amide with lithium-aluminumhydride in an anhydrous organic solvent which is inert under the reaction conditions, as the reaction medium, and at an elevated temperature, and isolating the resultant aforesaid pyridine.

10. A process for the preparation of fi-dimethylaminoethyl-benzhydryl ether which comprises reducing diphenylmethoxyacetic acid-dimethyl-amide to the said a fl-dimethylaminoethyl-benzhydryl other by reacting the diphenylmethoxy-acetic acid-dimethyl-amide with lithium-aluminum-hydride in an anhydrous organic solvent which is inert under the reaction conditions, as the reaction medium, and at an elevated temperature, and isolating the resultant B-dimethylaminoethyl-benzhydryl ether.

References Cited in the file of this patent UNITED STATES PATENTS 2,310,167 Carlson Feb. 2, 1943 2,349,318 Westphal May 23, 1944 2,371,694 Kuhn Mar. 20, 1945 OTHER REFERENCES 

1. A PROCESS FOR THE PREPARATION OF AN AMINE, WHICH COMPRISES REDUCING A CARBOXYLIC AND AMIDE CONTAINING AT LEAST ONCE THE 